Enantioselective Formal C(sp3)?H Bond Activation in the Synthesis of Bioactive Spiropyrazolone Derivatives

Article abstract of DOI:10.1002/anie.201811041

Herein, we report the first enantioselective annulation of α-arylidene pyrazolones through a formal C(sp³)?H activation under mild conditions enabled by highly variable Rh^III-Cp^x catalysts. The method has a wide substrate scope and proceeds with good to excellent yields and enantioselectivities. Its synthetic utility was demonstrated by the late-stage functionalization of drugs and natural products as well as the preparation of enantioenriched [3]dendralenes. Preliminary biological investigations also identified the spiropyrazolones as a novel class of Hedgehog pathway inhibitors.

Full text of DOI:10.1002/anie.201811041

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Accepted Article
Title: Enantioselective Formal C(sp3)-H Bond Activation in the
Synthesis of Bioactive Spiropyrazolone Derivatives
Authors: Herbert Waldmann, Houhua Li, Rajesh Gontla, Jana Flegel,
Christian Merten, Slava Ziegler, and Andrey P. Antonchick
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10.1002/anie.201811041
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Enantioselective Formal C(sp3)-H Bond Activation in the
Synthesis of Bioactive Spiropyrazolone Derivatives
Houhua Li,[a] Rajesh Gontla,[a] Jana Flegel,[a,b] Christian Merten,[c] Slava Ziegler,[a] Andrey P.
Antonchick,*[a,b] and Herbert Waldmann*[a,b]
Abstract: Herein we report the first enantioselective annulation of -
arylidene pyrazolones through a formal C(sp3)-H activation under mild
conditions enabled by highly variable Rh(III)-Cpx catalysts. The
method has wide substrate scope proceeds with good to excellent
yields and enantioselectivity. Its synthetic utility was demonstrated by
late-stage functionalization of drugs and natural products as well as
preparation of enantioenriched [3]-dendralenes. Preliminary biological
investigation also identified the spiropyrazolones as a novel class of
Hedgehog pathway inhibitors.
Rh(III)-catalyzed C-H bond activation followed by an annulation
reaction with alkynes using cyclopentadienyl (Cp) rhodium(III)
complexes as precatalysts has been explored as a rapid
approach to construct various heterocycles and carbocycles.[1-4]
Enantioselective variants have only become possible since the
introduction of chiral C2-symmetric Cpx ligands by Cramer et al.,
and of an artificial Rh(III)-containing metalloenzyme by Ward and
Rovis et al.[5-10] Thereafter, You et al. reported the first asymmetric
annulative dearomatization reaction of β-naphthols with alkynes
using chiral Rh(III)-Cpx catalysts (Scheme 1a).[7l] In addition,
carbonyl-directed
Rh(III)-catalyzed
enantioselective
C-H
activation/spiroannulation reactions have been developed by Lam
et al. followed by Yu et al.[7h,n] These spiroannulation reactions
provide unique access to novel classes of enantioenriched
spirocycles containing all-carbon quaternary centers. Current
enantioselective variants all include direct activation of aromatic
C(sp2)-H bonds under relatively demanding reaction conditions
(Scheme
1a).[7h,l,n]
Rh(III)-catalyzed
enantioselective
spiroannulation reactions through activation of alkenyl C(sp2)-H
and alkyl C(sp3)-H bonds still stand as a great challenge. Relevant
racemic examples have already been demonstrated recently
(Scheme 1b).[3a,b,d]
Scheme 1. Enantioselective C-H Activation/Spiroannulation Reactions Using
Rh(III)-Cpx Catalysts.
[a]
Dr. H. Li, Dr. R. Gontla, J. Flegel, Dr. S. Ziegler, Dr. A. P.
Antonchick, Prof. Dr. H. Waldmann
Max-Planck-Institut für Molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
J. Flegel, Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Technische Universität Dortmund
Fakultät Chemie und Chemische Biologie
Otto-Hahn-Strasse 4a, 44227 Dortmund (Germany)
Dr. C. Merten
Recently we reported a novel class of piperidine-fused Cpx
ligands.[10a,11] We envisaged that the above-mentioned
enantioselective spiroannulation reactions could be steered
efficiently using our highly variable Rh(III)-Cpx catalysts (Scheme
1c). Here we describe the first enantioselective annulation of -
arylidene pyrazolones through a formal C(sp3)-H activation under
mild conditions enabled by Rh(III)-Cpx catalysts.[12]
[b]
[c]
Ruhr-Universität Bochum
Lehrstuhl für Organische Chemie II
Universitätsstrasse 150, 44801 Bochum (Germany)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201811041
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Based on previous reports,[3d] a putative mechanism was
proposed.[14] A six-membered rhodacycle intermediate is initially
formed through an enol-directed formal C(sp3)-H activation. In the
following alkyne insertion step, the C−C bond formation occurs
preferentially at the alkyne carbon adjacent to the alkyl group,
thus affords spiropyazolone 4a as a single regioisomer (> 20:1
r.r.). The absolute configuration of product (4a) was determined
to be (S) by means of vibrational circular dichroism (VCD)
spectroscopy.[14]
Table 1. Optimization of reaction conditions[a]
Entry
Cat.
Solvent
T (C)
Yield (%)[b]
ee (%)[c]
1
3a
3a
3a
3b
3c
3d
3e
3e
3e
MeCN
MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
80
23
23
23
23
23
23
0
56%
18%
86%
46%
57%
64%
82%
70%
<10
69
2
75
3
75
4
81
5
84
6
84
7[d]
8[d]
9[e]
86
91
0
n.d.[f]
[a] Reaction conditions: 1a (0.15 mmol), 2a (0.10 mol), 3 (5 mol%), Cu(OAc)2
(2 equiv) in the indicated solvent (4.0 mL), under inert atmosphere unless
otherwise noted. [b] Isolated yields. [c] Determined by chiral HPLC. [d] Using
2 equiv of 1a. [e] Under O2 atmosphere. [f] n.d. = not determined.
Initially, -arylidene pyrazolone (1a) was chosen as model
substrate (Table 1).[3d,13] The oxidative annulation reaction with
the nonsymmetrical alkyne (2a) proceeded smoothly at 80 °C
using 5 mol% of 3a, albeit with only 69% ee (entry 1). Drastically
reduced reactivity was observed at ambient temperature (entry 2).
Gratifyingly, upon solvent screening, methanol was found to
greatly facilitate the annulation reaction at 23 °C with comparable
enantioselectivity (entry 3). We next screened our highly modular
and structurally variable Rh(I)-Cpx catalyst library. Compared to
catalyst 3a and other structurally similar analogues, pseudo C2-
symmetric Cpx ligands 3b-3e proved to be superior in terms of
induction of enantioselectivity, although slightly lower reactivity
was observed (entries 4-7). Fine-tuning of catalysts through
replacement of the 4-fluorophenyl group with a 2-naphthyl
substituent afforded 3e as most advantageous Rh(I)-Cpx catalyst
(entry 7). Of note, 3e stands as a new Rh(I)-Cpx catalyst which
has not been reported before. Finally, the model reaction
proceeded well at 0 °C and afforded the desired spiropyrazolone
(4a) with 91% ee (entry 8). The reaction was drastically prohibited
in the presence of O2 under otherwise identical reaction
conditions (entry 9).[7l]
Scheme 2. Substrate scope of the reaction. Reaction conditions: 1 (0.20 mmol),
2 (0.10 mol), 3e (5 mol%), Cu(OAc)2 (2 equiv) in MeOH (4.0 mL) at 0 °C under
inert atmosphere for 72 h. [a] Using 10 mol% of 3e.
Investigation of the substrate scope using substituted -
arylidene pyrazolones (1a-m) under optimal reaction conditions
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10.1002/anie.201811041
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revealed that both electron-withdrawing and electron-donating
groups on the ortho-, para-, and meta-position were well tolerated
and delivered the desired products with good to excellent
enantioselectivity (Scheme 2, 4a-m). In some cases, the reaction
outcome was found to be sensitive to the presence of ortho-
substituents presumably due to steric hindrance, and in these
cases 10 mol% of 3e was required (4g, 4i, 4k).
Various alkynes (2a-j) were afforded the desired
spiropyrazolones with enantioselectivities of up to 97% ee
(Scheme 2, 4n-4y). For the annulation of symmetrical aryl/aryl
alkynes (4r, 4s) 10 mol% of 3e was specifically required. When a
more challenging symmetric alkyl/alkyl alkyne was applied, the
product 4t was formed smoothly, albeit with low enantioselectivity
(34% ee). Nonetheless, nonsymmetrical alkynes including
aryl/alkyl (4n-q), vinyl/alkyl (4u, 4v), and heteroaryl/alkyl alkynes
(4x, 4y) were all excellent reaction partners. Interestingly, when
1,4-diphenylbutadiyne was tested, mono annulation product (4w)
was isolated exclusively in 93% ee and no double annulation
product was detected. Again, for all annulation reactions with
nonsymmetrical alkynes mentioned above, regioselectivity was
excellent and only a single regioisomer was detected (> 20:1 r.r.).
Finally, we performed late-stage functionalization studies of
drugs and natural product derivatives.[15] As shown in Scheme 3a,
alkynes were prepared from (R)-(-)-deprenyl (a selective
Monoamine Oxidase B inhibitor), estrone and (+)--tocopherol
and then carefully evaluated. To our delight, in all cases we
obtained exclusively a single diastereoisomer (>95:5 d.r.) upon
treatment with catalyst 3e. Furthermore, catalyst-directed
diastereoselective annulation reactions proceeded well, and the
other diastereoisomers were formed predominantly (>95:5 d.r.) by
switching the catalyst to ent-3e.[16]
[3]-Dendralenes have gained widespread attention,[17] as they
are valuable building blocks for the rapid construction of polycyclic
frameworks through multiple cycloaddition sequences.[18] To
further demonstrate the synthetic utility of our annulation reaction,
we conducted product diversifications through a one-pot allylic
alcohol oxidation-Wittig reaction of 4a (Scheme 3b).[19]
Accordingly, a series of unprecedented enantioenriched [3]-
dendralenes was obtained using various Wittig reagents with
good to excellent yields and enantioselectivity. Of special note,
the Corey-Fuchs reaction was also compatible with this protocol
and gave dibromo [3]-dendralene (6g) in 59% isolated yield. Upon
treatment with PTAD (4-phenyl-1,2,4-triazoline-3,5-dione), further
diversification of [3]-dendralene (6a) could be realized to afford
the cycloaddition adduct 7 through Diels-Alder reaction.
To investigate whether the compound collection modulates
biological pathways, 72 spiropyrazolones were synthesized and
subjected to different cell-based screens, including an osteoblast
differentiation assay that indirectly monitors Hedgehog (Hh)
signaling activity in pluripotent mouse mesenchymal C3H10T1/2
cells upon stimulation with purmorphamine.[20] Hh signaling is
essential for embryonic development and highly important for
stem cell homeostasis and tissue regeneration.[21,22] Constitutive
activation of Hh signaling is associated with the development and
Scheme 3. Late-stage functionalization and product diversification. [a] Reaction
conditions: 1 (0.20 mmol), 2 (0.10 mol), 3e or ent-3e (5 mol%), Cu(OAc)2 (2
equiv) in MeOH (4.0 mL) at 0 °C under inert atmosphere for 72 h. [b]
Diastereomeric ratios (d.r.) were determined based on 1H NMR analysis of
crude reaction mixtures. [c] Diastereomeric ratios (d.r.) were determined by
chiral HPLC. 1,2-DCE = 1,2-dichloroethene.
progression of various types of
cancer, including
medulloblastoma and basal cell carcinoma.[22,23] Therefore, novel
small-molecule modulators of the Hh pathway are in high
demand.[22]
Gratifyingly, several spiropyrazolones inhibited osteogenesis
with half-maximal inhibitory concentrations (IC50) in the low
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10.1002/anie.201811041
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osteogenic marker alkaline phosphatase.[24] The most potent
compound 4f inhibited Hh-dependent osteogenesis with a half
maximal inhibitory concentration (IC50) of 3.6 ± 0.8 µM. To confirm
the Hh inhibition, compound 4f was additionally characterized in
an orthogonal, GLI-dependent reporter gene assay using Shh-
LIGHT2 cells.[25] In this assay, compound 4f inhibited the GLI-
dependent expression of the reporter firefly luciferase with an IC50
of 8.8 ± 0.5 µM.[14] Therefore, the chemotype defined by
spiropyrazolones defines a structurally novel class of Hedgehog
pathway inhibitors.
In summary, we demonstrated the first enantioselective
annulation of -arylidene pyrazolones through a formal C(sp3)-H
activation under very mild conditions enabled by highly variable
Rh(III)-Cpx catalysts. The method gave access to a set of
structurally diverse spiropyrazolones containing all-carbon
quaternary centers in high yields and with high enantioselectivity.
Preliminary biological investigation in different cellular assays led
to the identification of the spiropyrazolones as a novel class of
Hedgehog pathway inhibitors.
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Acknowledgements
This work was supported by the Max-Planck-Gesellschaft. We
thank Dr. Sonja Sievers and the compound management and
screening center (COMAS) for compound screening, Dr. Zhi-Jun
Jia (Caltech) and Dr. Saad Shaaban for helpful discussions. H. L.
is grateful to the Swiss National Science Foundation (SNSF) for
an Early Postdoc. Mobility fellowship (P2GEP2_168250). C.M.
thanks the FCI for a Liebig Fellowship and the Deutsche
Forschungsgemeinschaft (DFG) for support through the Cluster
of Excellence RESOLV (“Ruhr Explores Solvation”, EXC 1069).
This research was supported by the European Research Council
under the Seventh Framework Programme of the European
Union (FP7/2007-2013; ERC Grant 268309 to H.W.) and by the
Max Planck Society.
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The authors declare no conflict of interest.
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Keywords: C-H activation • Enantioselective catalysis •
Rhodium • Spiropyrazolones • Hedgehog pathway inhibitors
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H. Li, R. Gontla, J. Flegel, C. Merten, S.
Ziegler, A. P. Antonchick,* and H.
Waldmann*
Page No. – Page No.
Enantioselective Formal C(sp3)-H
Bond Activation in the Synthesis of
Bioactive Spiropyrazolone
Derivatives
The first Rh(III)-catalyzed enantioselective annulation of -arylidene pyrazolones
through a formal C(sp3)-H activation under very mild conditions was developed
using a novel chiral Cpx ligand, yielding a novel class of Hedgehog pathway
inhibitors.
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